Abstract

In addition to the well-characterized interaction with classical and novel protein kinase C (PKC) isozymes, the phorbol ester tumor promoters bind to other receptors lacking kinase activity. Among these novel phorbol ester receptors, two families of proteins may play a role in the regulation of cell growth and malignant transformation: chimaerins and ras guanyl-releasing protein (ras-GRP). These proteins possess a single copy of the C1 domain that is involved in binding of phorbol esters and the lipid second messenger diacylglycerol. Four isoforms of chimaerins (alpha1-, alpha2-, beta1-, and beta2-chimaerins) have been isolated to-date, all of them possessing GTPase-activating protein activity for Rac, a small GTP-binding protein that controls actin cytoskeleton organization, cell-cycle progression, adhesion, and migration. Ras-GRP is a guanine nucleotide exchange factor for ras and promotes malignant transformation in fibroblasts in a phorbol ester-dependent manner. The C1 domain in Ras-GRP may, therefore, have a dominant role in Ras-GRP activation and is essential for phorbol ester-dependent activation of downstream effectors of ras, i.e., the mitogen-activated protein kinase cascade. Thus, a novel concept emerges in which phorbol esters may exert cellular responses through pathways not involving phorbol ester-responsive PKC isozymes. The discovery of "nonPKC" phorbol ester receptors adds an additional level of complexity to the understanding of phorbol ester effects and the molecular mechanisms of carcinogenesis.